ABSTRACT Neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) are a major source of disability and loss of potential, as well as emotional and financial hardship. Primary prevention of these disorders is of great public health importance, calling for the identification of modifiable risk factors, such as environmental chemical exposures. ASD and ADHD are both heritable but there is growing evidence that environment plays a role, and that environmental impact may be influenced by genetics. Traffic-related air pollutants, including fine particulate matter (PM2.5) and nitrogen dioxide (NO2) have biological evidence of neurotoxicity and human evidence that they may be risk factors for ASD and ADHD. Only two prior studies have considered the influence of genetics on air pollutant risk in neurodevelopmental disorders ? each addressing a single gene ? despite the fact that gene*environment investigation can improve ability to detect the impact of environmental chemicals and add pathophysiological insights. Prior studies are also limited in failing to consider co-diagnosis of ASD and ADHD, which is common, and other sub-phenotypes that may better reflect etiologically homogenous groups impacted by air pollutant exposure. The objective of this application is to conduct the largest single study of air pollutants with ASD and ADHD to date, in the context of genetic variation. The central hypotheses are that higher exposure during critical developmental windows to PM2.5 and NO2 will be associated with ASD and ADHD, the associations will be influenced by genetic factors, and will vary according to neurodevelopmental sub- phenotype. Our aims are: SA1: Deepen the mechanistic understanding of air pollutant risk on ASD, SA2: Clarify a potential role of air pollutant risk in ADHD, and SA3: Investigate the specificity of neurodevelopmental phenotypic subgroup associations with air pollutants, leading to cross-disorder insights. For each aim, we will (A) estimate air pollutant main effects, (B) account for child and family genetic modification of air pollution effects using a multi-faceted targeted approach among hundreds of loci, including genes related to exposure biology and neurodevelopment, and (C) estimate these associations in an exploratory genome-wide agnostic analysis using all available genetic markers. We will use a large, population-based study in Denmark with existing genome-wide genotyping data ? iPSYCH, including 16,146 children with ASD, 18,726 with ADHD (3033 with both), and 28,768 controls. We will add innovative well- validated weekly estimates of PM2.5 and NO2 air pollution exposures during critical developmental periods at both residential and employment locations. This work introduces key innovations including incorporation of novel genetic markers in exposure risk assessment and considering neurodevelopmental sub-phenotypes. It is significant in addressing modifiable causes of developmental disabilities, leading to elucidation of pathogenic mechanisms and specificity of effects, accelerating discovery for prevention and treatment.